Pharmacokinetic and pharmacodynamic characteristics of subcutaneously applied PTH-1–37

Abstract

Exogeneous delivery of parathyroid hormone fragments has become a novel treatment moiety for osteopenic conditions. The presented study was performed to assess the pharmacokinetic and pharmacodynamic properties of subcutaneously applied human hPTH-1–37 in comparison to hPTH-1–34 in healthy postmenopausal women. In total, 33 subjects participated in the study (age range: 57, 41–71 years, duration of postmenopausal state: 10, 2–28 years, BMI (mean±STD): 27.0±2.8kg/m2). The volunteers were randomized to either receive 10µg, 20µg, or 40µg of hPTH-1–37, 20µg hPTH-1–34, or placebo. Observation parameters were: adverse events and serum concentrations of hPTH-1–37, hPTH-1–34, hPTH-1–84, calcium, and cAMP. Both investigated PTH fragments showed fast absorption from the subcutaneous tissue. Tmax following hPTH-1–37 application was reached 44±3min after dosing hPTH-1–34 50±9min (p<0.05) and both PTH fragments had receded to baseline levels within 360min after administration (T1/2: hPTH-1–37: 63±5min; hPTH-1–34: 50±8min, p<0.05). The bioavailability of hPTH-1–37 relative to hPTH-1–34 as calculated from the AUC values was 68%. The Cmax values increased in a dose dependent manner (hPTH-1–37: 10µg: 27±7 pg/ml; 20µg: 71±25 pg/ml; 40µg: 127±37 pg/ml; hPTH-1–34, 20µg: 104±12 pg/ml). A dose response relationship was also seen for the increase in calcium after 6 hrs, while hPTH-1–84 was almost equally suppressed by all active PTH fragment concentrations. Only few and minor adverse events were reported that are known side effects from PTH treatment (headache, nausea etc.). In conclusion, in comparison to hPTH-1–34, hPTH-1–37 shows the same pharmacokinetic and pharmacodynamic properties and an acceptable relative bioavailability. hPTH-1–37 is an adequate future candidate for treatment of osteoporosis and other osteopenic conditions.